POS0528 EARLY OPTIMISATION OF METHOTREXATE THERAPY PREVENTS DIFFICULT-TO-TREAT RHEUMATOID ARTHRITIS: A SINGLE-CENTRE, RETROSPECTIVE COHORT STUDY
Authors: A. Giollo, M. Zen, M. Larosa, F. Arru, K. Botsios, A. Calligaro, A. Doria
Journal: Annals of the Rheumatic Diseases (2022)

Background According to the current EULAR recommendations for the management of rheumatoid arthritis (RA), methotrexate (MTX) should be started as soon as RA is diagnosed and rapidly optimized to achieve remission. Nonetheless, it has been estimated that a difficult-to-treat (D2T) disease occurs in 3-10% of RA patients 1 . Herein, we hypothesized that D2T-RA can be prevented with an optimal MTX treatment in early stages. Objectives The main objective of this study was to demonstrate an association between successful optimization of MTX treatment within two years of RA diagnosis and development of a status of D2T-RA later in the disease course. Methods In 2016 we started a ‘Refractory RA’ clinic at the Rheumatology Unit, University of Padua, Italy. In this retrospective cohort study conducted in December 2021, we enrolled patients fulfilling both the ACR/EULAR 2010 criteria for RA and the EULAR definition of D2T-RA 2 diagnosed after 2000. We compared D2T-RA patients with non-D2T-RA controls from the same clinic having similar sex distribution and year of diagnosis. The primary outcome was the status of DT2-RA. The exposure was ‘MTX optimization’ after two years from diagnosis, as assessed with a numeric score (the sum of the following binary variables concerning MTX therapy: started within 3, 12 or 24 months from diagnosis; adequate dose (≥15 mg weekly); treatment duration≥6 months; early intolerance (≤3 months); range 0 to 6, with higher scores reflecting better optimization). We used multiple logistic regression analysis to examine the association (odds ratio (OR)) between MTX optimization scores and the outcome, controlling for potential modifiers (age, sex, body mass index, age at onset, and anti-citrullinated peptides antibodies [ACPA]). Results There were 37 DT2 RA patients and 107 non-D2T RA controls for the analysis (mean (SD) disease duration 12.8 (4.1) vs. 12.6 (4.6), p=0.621). Per protocol, gender (females 77.3 vs. 82.0%, p=0.247) and year of diagnosis (median [25th, 75th percentile]: 2008 [2004, 2011] vs. 2008 [2003, 2012]) were comparable between groups. Optimization of MTX therapy was poor overall, yet MTX optimization scores were significantly higher in D2T-RA than in non-D2T-RA patients (1.06 (0.21) vs. 0.56 (0.14), p&lt;0.001). In multiple logistic regression, MTX optimization was protective against DT2-RA. Indeed, the likelihood of D2T-RA was decreased by 34%-54% according to MTX optimization scores. Other disease characteristics significantly associated with D2T-RA were an older age at diagnosis and female sex (Table 1). In December 2021 (last follow-up), D2T-RA patients were receiving a significantly higher daily dose of prednisone (4.3 (1.4) vs. 0.5 (0.2), p&lt;0.001), and had a numerically greater burden of comorbidities (median 3 [1, 4] vs. 2 [1, 3], p=0.252) and disease activity (DAS28-ESR: 3.41 (0.40) vs. 2.6 (0.19), p=0.053) than non-D2T-RA patients. Table 1. Early factors associated with difficult-to-treat rheumatoid arthritis (multivariable logistic regression) B SE P-value Odds ratio 95% IC MTX optimization score -0.599 0.092 &lt;0.001 0.549 0.459, 0.657 Age, years 0.033 0.008 &lt;0.001 1.034 1.017, 1.051 Sex (female vs males) 0.723 0.287 0.012 2.061 1.174, 3.615 BMI, kg/m 2 -0.006 0.018 0.748 1.006 0.970, 1.043 ACPA (positive vs negative) 0.431 0.2450 0.079 1.539 0.952, 2.487 ACPA, anti-citrullinated peptide antibodies; B, unstandardised beta coefficient; BMI, body mass index; MTX, methotrexate; SE, standard error. Conclusion DT2-RA may be prevented by optimization of MTX therapy within two years of RA management. References [1]de Hair MJH, Jacobs JWG, Schoneveld JLM, van Laar JM. Difficult-to-treat rheumatoid arthritis: an area of unmet clinical need. Rheumatology (Oxford);57(7):1135-1144. [2]Nagy G et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis 2021;80:31-35. Disclosure of Interests Alessandro Giollo Consultant of: Galapagos, Novartis, Eli-Lilly, Margherita Zen: None declared, Maddalena Larosa: None declared, Federico Arru: None declared, Konstantinos Botsios: None declared, Antonia Calligaro: None declared, Andrea Doria Consultant of: GSK, Pfizer, Eli Lilly, Roche, Janssen, AstraZeneca, Galapagos.